Aznan Lelo

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera
Utara
2 April 2011, MEDAN
PAIN 2011, Medan

Surgical Inflammatory Pain

functio
laesia

inflammation
tumor

acute

pain

rubor
calor

chronic

Inflammatory mediator
and its actions
Mediator

Vascular
VasoChemo
Pain
permeability dilatation taxis

Histamine Serotonin
Bradykinin +++
Prosta+
glandin
Leukotriene

++
+/+++

+++

+++

+++

Classification of some major

features of pain
Type

Duration

Characteristics

Cells

Adaptive
response

Examples

Acute

Seconds Proportional

Nociceptive

Withdrawal,
escape

Contact with
hot surface

Subchronic

Hours to
days

Hyperalgesia,
Allodynia,
Spontaneous
pain

Nociceptive
Neurogenic

Quiescence,
Avoidance of
contact with
injured
tissues

Inflammatory
wound

Chronic

Months to
years

Hyperalgesia,
Allodynia,
Spontaneous
pain
Affective
component

Nociceptive
Neurogenic

Psychological Arthritis, CNS

and cognitive injury,
metastatic
disease

to the cause

Nociceptive Pain
Examples:
Post-surgical
metastatic bone pain
musculoskeletal pain
arthritic pain

What to know
Responds to NSAIDs and Opioids

Factors that modify postoperative pain :

1. Site, nature and duration of surgery.
2. Type and extent of incision.
3. Physiologic and psychologic makeup of
the patient.
4. Pre operative preparation of the patient.
5. Presence of complications of surgery.
6. Anesthetic management.
7. Quality of perioperative care.
8. Preoperative treatment of painful stimuli .

Pain Management
Goals of Pain Management

o Relieve suffering
o Increase functional capacity
o Improve quality of life
Ways to advocate for Pain
Management
o Dont use placebos
o Promote pain education with all
disciplines

Pathophysiology of acute
inflammatory pain
Pain mediators released in acute
inflammatory pain
Bradykinin
Prostaglandin

Enzyme involved in prostaglandin

synthesis
COX 1 & COX-2

Half-life of prostaglandin
Seconds or minutes

COX-1/COX-2 selectivity of NSAIDs

COX-2
selective

Pref.
COX-2

non
selective

Pref.
COX-1

COX-1
selective

analgesic
NNT
anti-inflammation

COX-1 Inhibition at Therapeutic COX-2 Inhibition

in a Human Whole Blood Assay
ketorolac

suprofen
flurbiprofen
aspirin

ketoprofen

ampyrone
ibuprofen
naproxen
tolmetin
indomethacin
zomepirac
fenoprofen
sodium salicylate
niflumic acid
diflunisal
meclofenamate
piroxicam
sulindac sulphide
diclofenac
tomoxiprol
celecoxib
nimesulide
meloxicam
etodolac
NS-398
rofecoxib

20

40

60

80

100

120

% Inhibition COX-1 when COX-2 inhibited by 80%

Warner et al. PNAS 1999; 96: 7563-7568

COX hypothesized centrally involves

in inflammatory pain

Willoughby DA, et al. COX-1, COX-2, and COX-3 and the future
treatment of chronic inflammatory disease. Lancet 355: 646-

Zhu X, Conklin DR, Eisenach JC.

Preoperative Inhibition of Cyclooxygenase-1
in the Spinal Cord Reduces Postoperative Pain
Anesth Analg 00:1390-3,2005

5 minutes before surgery, rats received

intrathecally:

the COX-1 preferring inhibitor, ketorolac,

the specific COX-1 inhibitor, SC-560,
the specific COX-2 inhibitor, NS-398, or vehicle.

Ketorolac and SC-560 increased withdrawal

threshold to mechanical stimulation, but NS-398
had no significant effect.
These results suggest that COX-1 plays an
important role in spinal cord pain processing and
sensitization after surgery and that preoperative
intrathecal administration of specific COX-1
inhibitors may be useful to treat postoperative pain.

Ng A, Temple A, Smith G, Emembolu J

Early analgesic effects of parecoxib versus ketorolac

following laparoscopic sterilization:
a randomized controlled trial
British Journal of Anaesthesia, 92(6):846-9,2004

double blind RCT, early postoperative pain.

36 ASA I/II patients who received a standardized general
anaesthetic for laparoscopic sterilization allocated
randomly:
parecoxib 40 mg i.v. or
ketorolac 30 mg i.v., at induction.

After surgery, patients were assessed on awakening and

then at 1, 2, and 3 h. Abdominal pain at rest and on
inspiration, in addition to nausea and sedation were
assessed on a 100 mm visual analogue scale.
parecoxib 40 mg i.v. given at induction of anaesthesia
was less effective than ketorolac 30 mg i.v., in the first
hour after laparoscopic sterilization.

Reuben SS, Buvanendran A, Kroin JS, Steinberg RB.

Postoperative modulation of central nervous system

prostaglandin E2 by cyclooxygenase inhibitors after
vascular surgery.
Anesthesiology. 104(3):411-6,2006.

Cerebrospinal fluid prostaglandin E2 is elevated

in patients after lower extremity vascular
surgery.
Postsurgical intravenous administration of
o the cyclooxygenase 1 inhibitor ketorolac (30 mg), and
o the cyclooxygenase 2 inhibitor parecoxib (40 mg)

reduces

cerebrospinal fluid prostaglandin E2 concentration

and
postoperative pain.

Current view in selecting analgesic and

anti-inflammatory drugs
Efficacy (indication)
Safety (side effect)

Not only GI toxicity

Cardiovascular toxicity
Renal toxicity
Bleeding
Bone healing impairment etc

Suitability (contra-indication)
Availability
Pharmacokinetics and drug interaction
Daily cost
Evidence based medicine

Chemical structure of
NSAIDs
CO2H
O

H
N

CO2H

CO2H

HO

acetylsalicylic acid

acetaminophen

ibuprophen

ketoprophen

aspirin

Tylenol

Motrin, Nuprin

Orudis
Cl

CO2H
MeO

CO2

H
N
Cl

naproxen

diclofenac

Naprosyn, Alleve

Cataflam, Voltaren
O
Cl

N
CO2H

MeO
CO2H

ketorolac

indomethacin

Toradol

Indocin

Ketorolac tromethamine
a member of the pyrrolo-pyrrole group of
NSAIDs.
()-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic
acid, 2-amino-2-(hydroxymethyl)-1,3-propanediol.

a racemic mixture of [-]S- and [+]Renantiomeric forms, with the S-form having
analgesic activity.
Protein binding > 99%, half-life 4 6 hours
Hepatic metabolism and renal excretion

Pharmacokinetic Parameters (Mean SD)

po, im and iv doses of Ketorolac Tromethamine
Route of administration

po

im

Iv

Pharmacokinetic Parameter

10 mg

15 mg

15 mg

Bioavailability (extent)

100%

100%

100%

Tmax1 (min)

44 34

33 21**

1.1 0.7**

0.87 0.22

1.14
0.32**

2.47
0.51**

Cmax (mcg/ml)[steady state qid]

1.05
0.26**

1.56
0.44**

3.09
1.17**

Cmin3 (mcg/ml)[steady state qid]

0.29
0.07**

0.47
0.13**

0.61
0.21**

Cavg4 (mcg/ml)[steady state qid]

0.59
0.20**

0.94
0.29**

1.09
0.30**

Vbeta5 (L/kg)

0.175
0.039

0.1750.039

0.210
0.044

Cmax2(mcg/ml)[single dose]

Summary of analgesic, anti-inflammatory and

antipyretic activity of NSAIDs (ED50 in mg/kg)

NSAID

Analgesic

Anti-inflammatory

Antipyretic

ketorolac

0.7

0.9

indomethacin

2.1

diclofenac

0.4

naproxen

13

56

0.5

ibuprofen

45

10

piroxicam

100

1.7

tenoxicam

100

1.7

aspirin

228

162

18

Number-needed-to-treat (vs
placebo)
Oxford acute pain league table
www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html

Lumiracoxib 400 mg

1.7

Parecoxib iv 40 mg

2.2

Diclofenac 50 mg

2.3

Ibuprofen 400 mg

2.4

Ketorolac 10 mg

2.6

Morphine im 10 mg

2.9

Celecoxib 200 mg

2.9

Paracetamol 1000 mg

3.8

Tramadol 100 mg

5.0

95% Cl of the NNT

9 10

League table of percentage of patients

achieving at least 50% pain relief over 4-6 hours
in patients with moderate to severe pain, all oral
analgesics except IM morphine and pethidine and
ketorolac

J Barden, JE Edwards, HJ McQuay, RA Moore.

Oral valdecoxib and injected parecoxib

for acute postoperative pain:
a quantitative systematic review
BMC Anesthesiology 2003, 3:1

Rata-rata perbedaan intensitas

nyeri antar kelompok terapi
menurut waktu

Lidocaine (intraop) + Ketorolac (postop)

Groudine. Anesth Analg 1998; 86:235

VAS reduction (mm)

Rodriguez MJ, et al. Double-blind evaluation of short-term

analgesic efficacy of orally administered dexketoprofen
trometamol and ketorolac in bone cancer pain. Pain. 104(12):103-10,2003.

Jo YY, Hong JY, Choi EK, Kil HK.

Ketorolac or fentanyl continuous

infusion for post-operative analgesia
in children undergoing
ureteroneocystostomy.
Acta Anaesthesiol Scand. 2011 Jan;55(1):54-9.

Ketorolac was more effective in reducing

the frequency of bladder spasms and
rescue analgesic requirements.

Dawkins TN, Barclay CA, Gardiner RL,

Krawczeski CD.

Safety of intravenous use of

ketorolac in infants following
cardiothoracic surgery.
Cardiol Young. 2009 Feb;19(1):105-8.
Intravenous ketorolac appears to be safe
when used in infants less than six months of
age with biventricular circulations following
cardiothoracic surgery.

 Ketorolac is an acidic and COX-1 selective

NSAID
Ketorolac has a potent analgesic action,
comparable to morphine with an ideal
NNT value
Ketorolac is an safe analgesic, even for
infant undergoing surgery